ABSTRACT Hypertension is predicted to be the leading global cause of death and disability by the year 2020. The development of antihypertensive drugs has been dramatically less productive than expected, making new mechanistic insights into blood pressure regulation essential. This application will test the hypothesis that mechanoreceptor dependent sympathoinhibitory afferent renal nerve reno-renal reflexes suppress sympathetic outflow to the kidney to reduce ?1-adrenoceptor stimulated NCC-mediated sodium reabsorption and counter hypertension. These studies will employ our novel technique of selective afferent renal nerve ablation, direct mechano- and chemosensitive stimuli, and pharmacological tools in rat models of hypertension (Aims 1, 2 & 3), a unique mouse distal convoluted tubule cell line (Aim 3) and normotensive and hypertensive human patient samples (Aim 3) to delineate the integrated renal and sympathetic nervous system mechanisms that influence renal sodium reabsorption to regulate long term blood pressure. The following Specific Aims will be conducted to test this hypothesis: Specific Aim 1: The afferent renal nerve reno-renal reflex mediates sympathoinhibition and natriuresis to prevent the initiation of salt-sensitive hypertension. Specific Aim 2: That mechanoreceptor-dependent afferent renal nerve activation facilitates fluid and electrolyte homeostasis and blood pressure regulation. Specific Aim 3: That norepinephrine regulates NCC activity, via an ?1-adrenoceptor gated WNK1-OxSR1 signal transduction pathway, to mediate sodium homeostasis and long-term blood pressure regulation. These hypertension focused studies are central to the mission of the National Heart Lung and Blood Institute (NHLBI), which is to promote the prevention and treatment of heart, lung and blood disease, and directly support Goal 1 of the NHLBI Strategic Plan, which is to improve understanding of molecular and physiological basis of health and disease. These studies also directly address the 2014 NHLBI Salt in Human Health and Sickness Working Group recommendations for 1) a need to further illuminate the biological mechanisms and pathological processes to which salt may contribute, and 2) the identification of salt-sensitive hypertension as a priority research topic. Specific Aim 1 will establish a role of the afferent renal nerves in sodium excretion, sympathetic outflow and blood pressure regulation during acute and chronic challenges to salt and water balance. Specific Aim 2 will establish the renal mechanoreceptors as the site of afferent renal nerve signal propagation to the brain to facilitate sympathoinhibition and sodium excretion. Specific Aim 3 will establish the actions of the sympathetic nervous system release of norepinephrine to regulate the sodium chloride cotransporter, via a novel ?1- adrenoceptor signal transduction pathway in rat and human studies. Our studies, performed by a multidisciplinary collaborative research team, will potentially identify new therapeutic targets and/or personalized treatment paradigms for salt-sensitive hypertension ? meeting an urgent public health need for the 1 in 3 US adults currently living with essential hypertension.